FACULDADE DE MEDICINA DA UNIVERSIDADE DE COIMBRA

MESTRADO INTEGRADO EM MEDICINA – TRABALHO FINAL

DIOGO FILIPE DE ALMEIDA FERREIRA FERNANDES

Adequation of the therapeutic profile, co-morbidities and

personal habits of Brugada patients with ICD and its link to

dysrhythmic events

ARTIGO CIENTÍFICO ORIGINAL

ÁREA CIENTÍFICA DE FARMACOLOGIA

Trabalho realizado sob a orientação de:

PROF. DRA. NATÁLIA SOFIA CLÁUDIO ANTÓNIO

DRA. MARTA JESUS MADEIRA

NOVEMBRO/2017

Adequation of the therapeutic profile, co-morbidities and

personal habits of Brugada patients with ICD and its link to

dysrhythmic events

DIOGO FILIPE DE ALMEIDA FERREIRA FERNANDES

PROF. DRA. NATÁLIA SOFIA CLÁUDIO ANTÓNIO1,3

DRA. MARTA JESUS MADEIRA2,3

1 Hospital da Universidade, Centro Hospitalar e Universitário de Coimbra, Portugal

2Hospital Geral, Centro Hospitalar e Universitário de Coimbra, Portugal

3Faculdade de Medicina, Universidade de Coimbra, Portugal

Endereço de Correio Eletrónico: almeidafernandes.diogo@gmail.com

Index

Resumo ..................................................................................................................................4

Palavras-Chave .......................................................................................................................5

Abstract ..................................................................................................................................6

Keywords ...............................................................................................................................7

Abbreviations list ...................................................................................................................8

Introduction ............................................................................................................................9

Methods ............................................................................................................................... 11

Study design and Patient selection ................................................................................. 11

Data collection .............................................................................................................. 11

Data analysis ................................................................................................................. 12

Results.................................................................................................................................. 12

General description of the population ............................................................................ 12

Therapeutic profile since diagnosis ................................................................................ 14

Cardiac events and ICD therapies .................................................................................. 14

Comparison between patients with and without appropriate ICD therapies .................... 15

Discussion ............................................................................................................................ 16

Sample characteristics ................................................................................................... 16

Therapeutic profile ........................................................................................................ 17

Electrophysiological effects of the most taken non-recommended drugs ........................ 18

Type 2 DM and arrhythmic risk in Brugada syndrome ................................................... 18

Limitations .................................................................................................................... 19

Conclusion ........................................................................................................................... 20

Acknowledgments ................................................................................................................ 21

References ............................................................................................................................ 22

Picture Index

Figure 1 - Patient Stableelection ........................................................................................... 11

Figure 2 - Genetic testing and results .................................................................................... 14

Figure 3 - Non-recommended drugs taken ............................................................................ 14

Table Index

Table 1 - Baseline demographical and clinical characteristics ............................................... 13

Table 2 - Cardiac events and ICD therapies .......................................................................... 15

Table 3 - Relationship between appropriate ICD therapies and the different variables ........... 15

4

Resumo

Introdução: A síndrome de Brugada é uma doença hereditária associada a um aumento do risco

de morte súbita com possível necessidade de colocação de cardioversor-desfibrilhador

implantável (CDI) de forma a interromper os eventos disrítmicos. Os nossos objetivos foram

identificar possíveis desencadeadores de terapias apropriadas do CDI em doentes com síndrome

de Brugada e avaliar se o perfil terapêutico passado e atual é adequado à doença.

Métodos: Um total de 30 doentes com síndrome de Brugada submetidos a implantação de CDI

e seguidos no Centro Hospitalar e Universitário de Coimbra (CHUC) participaram neste estudo.

Foi recolhida informação acerca da história da sua doença, eventos cardíacos anteriores,

comorbilidades, medicação atual e passada e atividade física. O follow-up médio foi de

5.8 ± 5.3 anos. O CDI foi interrogado e foram registados os eventos arrítmicos e as terapêuticas

administradas. Por fim, comparámos a coorte que recebeu terapias apropriadas do CDI com os

restantes doentes para tentar identificar eventuais ligações entre as diferentes variáveis clínicas

e disritmias ventriculares potencialmente fatais.

Resultados: Mais de metade dos doentes (53.3%) tomou pelo menos um fármaco não

recomendado e 16.7% receberam terapias apropriadas do CDI, com uma incidência anual a

longo prazo de 4.0%/ano. Foi encontrada uma tendência para maior ocorrência de terapias

apropriadas do CDI em doentes que tomaram fármacos não recomendados (85.7% vs 45.5%,

p = 0.062). Nos doentes com diabetes mellitus tipo 2 a ocorrência de terapias apropriadas foi

significativamente superior à dos não diabéticos (33.3% vs 0.0%, p = 0.006).

Discussão e Conclusão: Este estudo revelou que ainda não existe o devido conhecimento das

restrições farmacológicas impostas pela doença. Um grande número de doentes tomou pelo

menos um fármaco não recomendado e este grupo apresentava uma tendência para receber mais

terapias apropriadas do CDI. A diabetes mellitus tipo 2 também parece estar associada a maior

ocorrência de disritmias ventriculares.

5

Palavras-Chave

Síndrome de Brugada, Cardioversor Desfibrilhador Implantável, Arritmia Cardíaca, Arritmias

Induzidas por Fármacos, Morte Súbita

6

Abstract

Introduction: Brugada Syndrome is a hereditary disease linked with an increased risk of sudden

death that may require an implantable cardioverter-defibrillator (ICD) in order to halt the

malignant arrhythmic events. Our objectives were to identify possible triggers for appropriate

ICD therapies in patients with Brugada Syndrome, focusing on their past and current therapeutic

profile.

Methods: Thirty patients with high-risk Brugada syndrome, with ICD implanted at the Coimbra

Hospital and University Centre, were enrolled. Patients were questioned about their Brugada

Syndrome history, previous cardiac events, comorbidities, present and past medication and

physical activity. Patients were followed-up during 5.8 ± 5.3 years. The ICD was interrogated

and arrhythmic events and device therapies were recorded. The cohort who received appropriate

ICD therapies was compared with the remaining patients to determine the potential link

between clinical variables and potentially fatal arrhythmic events.

Results: More than half of the patients (53.3%) took at least one non-recommended drug and

16.7% received appropriate ICD therapies, with a long-term rate of 4.0%/year. There was a

tendency for more appropriate ICD therapies in patients who took unsafe drugs (85.7% versus

45.5%, p = 0.062). Additionally, type 2 diabetic patients had significantly more appropriate

therapies than their counterparts (33.3% vs 0.0%, p = 0.006).

Discussion and Conclusion: This study revealed that the medical community is still unaware of

the pharmacological restrictions imposed by Brugada Syndrome. Patients who took

non-recommended drugs and patients with type 2 diabetes mellitus seem to have a higher risk

of ventricular arrhythmic events.

7

Keywords

Brugada Syndrome, Implantable Cardioverter-Defibrillator, Cardiac Arrhythmia,

Drug-induced Arrhythmias, Sudden Death

8

Abbreviations list

ATP Antitachycardia Pacing

BMI Body Mass Index

BrS Brugada Syndrome

DM Diabetes Mellitus

ECG Electrocardiogram

FH Family history

IPAQ International Physical Activity Questionnaire

METS Metabolic equivalents

PVT Polymorph Ventricular Tachycardia

SD Sudden Death

VF Ventricular Fibrillation

VT Ventricular Tachycardia

9

Introduction

Brugada Syndrome (BrS) is a hereditary disease described for the first time in 1992

characterized by an increased risk of ventricular arrhythmias and sudden death (SD) in patients

without structural heart disease.1–9

Recent studies estimate a global prevalence of 1 to 5 per 10.000 people.1–5,10,11 In Southeast

Asia and Japan the disease is considered endemic, having a prevalence as high as 10 to 12 per

10.000 people.1–5,7,10,12,13 However, since a great number of patients are asymptomatic and, as

a result, undiagnosed, these numbers may be even higher.3 Furthermore, BrS is more prevalent

in men.1,5,7,13 Nowadays, BrS is regarded has one of the main causes of sudden death in

otherwise healthy individuals with structurally normal hearts, especially in patients under 40

years old.1,4,5,14

In most cases the disease has an autosomal dominant mode of transmission with variable

penetrance1–5,7,8,11–14 and more than 20 genes have been identified.14 Mutation of SCN5A, a

gene encoding an α subunit of the cardiac sodium channel, is present in about 20% of the

patients.1,3–5,7,11–13 It is believed that genetic mutations occurring in this gene cause ionic

unbalances which form the basis for the symptoms and changes observed in BrS.1,3–5,7,11–13

Syncope is the most common form of presentation.1–5,7,8,11,14 Other possible symptoms are

sudden death,2–5,8,9,12,14 aborted sudden death,2,3,5,7,11,14 ventricular fibrillation (VF),2–7,14

polymorph ventricular tachycardia (PVT),2–6,14 nocturnal agonal respiration2–7,11 or

supraventricular arrhythmias with palpitations or dizinness,1–5,7,8,11 usually in men1,3–5,7,10–12

sleeping or resting2–5,7,10,11,13 with ages between 30 and 50 years old.1,3,4,7,10,11,13 Nevertheless,

most patients are asymptomatic at the time of diagnosis,1–5,11 being identified by chance or

during genetic screening of first degree relatives.

A HRS/EHRA/APHRS consensus in 2013 states that diagnosis is made through a

pathognomonic electrocardiogram (ECG), either spontaneous or induced with a Class I

10

antiarrhythmic drug.7 Other electrocardiographic signs may support the diagnosis and improve

risk stratification, such as early repolarization pattern1,6,11,12,14–16 (J wave, present in 10% of the

patients)11, aVR sign1,3,12,14,16, intraventricular conduction delay1,4,5,11,12,14,16 and increased QTc

interval.3 Patients with BrS also have a greater risk of developing atrial fibrillation,1–4,6,7,11,13,14

with some studies describing an incidence of 15 to 30%.3,4,6,11 Following diagnosis it is

necessary to stratify the risk of cardiac events and, consequently, identify the ones with

indication for an implantable cardioverter-defibrillator (ICD).1,3–5,10,11,17,18 This is the only

proven effective therapeutic strategy for the prevention of sudden cardiac death in BrS

patients.1,3–5,10,11,17 However, these patients are vulnerable to inappropriate shocks and may

require multiple device replacements during their life,7,19 leading to a lower quality of life.

Furthermore, BrS patients must adopt certain behaviors that diminish the probability of

arrhythmic events such as avoiding certain drugs,5,7,10,11,13,20,21 as the ones listed at

www.brugadadrugs.org,20,21 avoid cannabis13 and cocaine4,5,12,13 consumption, excessive

alcohol,4,5,10,12,13,22 high carbohydrate intake5,10 and very hot baths.5 These patients must

maintain a healthy and active lifestyle while respecting the restrictions imposed by their

disease.13 Vigorous exercise has also been linked with ventricular arrhythmias and an increase

in ST abnormalities.23

Given that BrS is one of the main causes of sudden cardiac death in young patients and that

there are many factors that may contribute to arrhythmic events, it is of the utmost importance

to investigate if medications and lifestyle are responsible for complications during long-term

follow-up.

Consequently, the objectives of this study were to identify possible triggers for appropriate ICD

therapies in BrS patients and evaluate the past and current medication impact on this

channelopathy.

11

Methods

Study design and Patient selection

The study employed a retrospective

observational design.

The study was conducted at the Coimbra

Hospital and University Centre (CHUC),

in Coimbra. Patients with a diagnosis of

BrS confirmed by two trained arrhythmologists and an ICD implanted in the time period

between January 2004 and March 2017 were included (Figure 1). The mean follow-up time was

5.8 ± 5.3 years.

The study was conducted in accordance to the Declaration of Helsinki and was approved by

Local Ethics Committee of the Coimbra Hospital and University Center. Each patient provided

an informed consent to participate in the study.

Data collection

Patients were questioned about BrS history (date of diagnosis, reason of diagnosis, FH of

sudden death), previous cardiac events (syncope and aborted sudden death), comorbidities (type

2 diabetes mellitus (DM), dyslipidemia, arterial hypertension, stroke, coronary heart disease,

acute myocardial infarction and heart failure), present and past medication (including the drugs

mentioned in www.brugadadrugs.org), personal habits (alcohol intake, cocaine and cannabis

usage, carbohydrate intake, hot baths) and current lifestyle (physical activity, smoking). They

were also asked to fill in the short form of the International Physical Activity Questionnaire

(IPAQ).

Furthermore, the ICD was interrogated and arrhythmic events and device therapies were

recorded and reviewed by two trained arrhythmologists.

Figure 1 - Patient Selection

12

Data analysis

The data were analyzed using IBM® SPSS® Statistics version 24.

First, we made a descriptive analysis of the different variables. We determined the mean and

standard deviation of the continuous variables and the relative frequency of the qualitative

variables.

A Mann-Whitney U test was used to compare quantitative variables between patients receiving

appropriate ICD therapies and the ones who did not receive any appropriate ICD therapies. The

Chi-squared test was employed to compare the same groups regarding qualitative variables. A

p-value inferior to 0.05 was considered statistically significant.

Results

General description of the population

A total of 30 BrS patients with an ICD were studied. Twenty-three of them were male (76.7%)

and 7 were female (23.3%). The mean age of the cohort was 55.2 ± 13.6 years old and the mean

body mass index (BMI) was 25.8 ± 3.3 kg/m2.

The demographic and clinical characteristics of the studied population are shown in Table 1.

Most patients studied had a spontaneous type 1 Brugada ECG (90.0%). Only 14 patients

(46.7%) were submitted to genetic testing (Figure 2).

In terms of clinical history, 7 patients (23.3%) had history of cardiac arrest before the diagnosis

and 19 (63.3%) referred past events of syncope. Fourteen patients (46.7%) had at least one

confirmed case of sudden death in first degree relatives.

Regarding electrocardiographic patterns, one patient (3.3%) had early repolarization, 7 (23.3%)

aVR sign, 11 (36.7%) intraventricular conduction defect and 4 (13.3%) documented persistent

or paroxysmal atrial fibrillation. In this cohort, the mean QTc interval in DII was

407.7 ± 26.2 ms.

13

The most common co-morbidity was dyslipidemia (16 patients, 53.3%) followed by

hypertension (10 patients, 33.3%). Concerning lifestyle, 11 patients (36.6%) were active or

former smokers, 8 (26.7%) consumed alcohol frequently, 4 (13.3%) had a high carbohydrate

intake and 1 (3.3%) admitted to taking very hot baths. The group of active and former smokers

smoked on average 11.4 ± 9.1 pack-year. Regarding physical exercise the mean metabolic

equivalents (METS) was 2575.8 ± 2430.8.

Table 1 - Baseline demographical and clinical characteristics

Total (n=30)

Value Proportion (%)

Heart rate (bpm) 71.7 ± 14.1

Brugada Type

Spontaneous type 1

Provoked type 1

27

3

90.0

10.0

Genetic test

Mutation detected (SC5NA)

14

3

46.7

21.4

Aborted sudden death 7 23.3

Syncope 19 63.3

FH of sudden death 14 46.7

ECG Data

Early repolarization

pattern

1 3.3

aVR sign 7 23.3

Intraventricular conduction

defect 11 36.7

QTc interval in DII (ms) 407.7 ± 26.2

Persistent/paroxysmal

atrial fibrillation 4 13.3

Comorbidities

Dyslipidemia 16 53.3

Type 2 DM 2 6.7

Hypertension 10 33.3

Stroke/Transient ischemic

attack 1 3.3

Smoking

Non-smoker

Active smoker

Former smoker

Unknown

11

4

7

8

36.7

13.3

23.3

26.7

14

Pack-year 11.4 ± 9.1

Alcohol consumption 8 26.7

High carbohydrate intake 4 13.3

Very hot baths 1 3.3

Physical exercise (METS) 2575.8 ± 2430.8

Sedentarism 12 40.0

BMI, body mass index; FH, family history; DM, diabetes mellitus; METS, metabolic

equivalents

Figure 2 - Genetic testing and results

Therapeutic profile since diagnosis

Sixteen patients (53.3%) had taken at least one drug that is contraindicated or should be avoided

since the diagnosis and 5 of them (16.7%) took a combination of them. The most prescribed

non-recommended drug in the studied cohort was metoclopramide (6 patients, 20%: Figure 3).

Figure 3 - Non-recommended drugs taken

Cardiac events and ICD therapies

Seven patients (23.3%) received ICD therapies during a mean follow-up of 5.8 ± 5.3 years

(Table 2). Five patients (16.7%) had appropriate shocks and 2 (6.7%) antitachycardia pacing

3 11 16

0 5 10 15 20 25 30 35

Genetic testing

SCN5A No gene identified No testing

3.3 3.3 3.3

6.7 6.7 6.7 6.7

13.3 13.3

20.0

0

5

10

15

20

25

PER

CEN

TAG

E (%

)

15

(ATP). The long-term rate of appropriate ICD therapies was 4.0%/year (2.9%/year for

appropriate shocks and 1.1%/year for ATP). There were 2 cases (6.7%) of inappropriate shocks

due to atrial fibrillation.

Table 2 - Cardiac events and ICD therapies

Total (n=30)

Value Proportion (%)

Appropriate shocks 5 16.7

ATP 2 6.7

Type of arrhythmia treated

VT

VF

4

3

13.3

10.0

Inappropriate shocks 2 6.7

ATP, antitachycardia pacing; VT, Ventricular tachycardia; VF, Ventricular fibrillation

Comparison between patients with and without appropriate ICD therapies

There were no statistically significant differences between the population who received

appropriate ICD therapies and the one who did not regarding age, BMI, physical activity

(METS) and QTc duration.

The Chi-squared test results are shown in Table 3. Patients with appropriate ICD therapies

during follow-up tended to be more frequently treated with non-recommended drugs than

patients without ICD therapies (85.7% versus 45.5%, p = 0.062). Additionally, patients with

type 2 DM showed a significantly higher proportion of adequate ICD therapies during

follow-up (33.3% versus 0.0%, p = 0.006).

Table 3 - Relationship between appropriate ICD therapies and the different variables

Adequate ICD therapies p-value

Yes (n = 7) No (n = 23)

Gender

Male/Female (%)

57.1/42.9

82.6/17.4

0.163

Mutation detected (%) 25.0 25.0 1.000

Early repolarization pattern (%) 0.0 4.8 0.557

aVR sign (%) 14.3 28.6 0.639

Intraventricular conduction defect (%) 14.3 47.6 0.118

Persistent/paroxysmal atrial fibrillation (%) 0.0 20.0 0.200

Syncope (%) 57.1 68.2 0.593

16

Aborted Sudden death (%) 28.6 22.7 0.753

FH of Sudden death (%) 42.9 55.0 0.580

Sedentarism (%) 75.0 50.0 0.364

Dyslipidemia (%) 100.0 60.0 0.121

Type 2 DM (%) 33.3 0.0 0.006

Hypertension (%) 60.0 33.3 0.271

Stroke/Transient ischemic attack (%) 0.0 4.8 0.557

Smoking (%)

Active smoker

Former smoker

Non-smoker

20.0

40.0

40.0

17.6

29.4

52.9

0.871

Alcohol consumption (%) 40.0 37.5 0.920

High carbohydrate intake (%) 25.0 18.8 0.780

Very hot baths (%) 0.0 6.3 0.608

Non-recommended drugs (%) 85.7 45.5 0.062

Discussion

The main findings of this study are: 1) a large proportion of high-risk BrS patients took at least

one unsafe drug in any moment after the ICD implantation, 2) patients who took at least one

non-recommended drug had a higher tendency for adequate ICD therapies and 3) type 2 DM

was associated with a higher rate of appropriate ICD therapies.

Sample characteristics

The cohort of patients studied was mainly male (76.7%), which goes in accordance with other

international studies regarding the prevalence of the disease.1,5,7,13 Only 21.0% of the patients

submitted to genetic test had an identifiable mutation, all in the SCN5A gene, a number similar

to the one demonstrated by other studies.1,3–5,7,11–13

Family history (FH) of sudden death and syncope1–5,7,8,11,14 remain two of the most important

clues for the diagnosis, being present respectively in 46.7% and 63.3% of the patients. Both the

early repolarization pattern (3.3%) and atrial fibrillation (13.3%) were less frequent in the

studied cohort than demonstrated in previous studies, which may be justified by the small size

of the sample. Consequently, these results demonstrate that almost all patients have a

background of familial sudden death or syncope that may provide an important clue to an early

diagnosis and lead to a successful prevention of SD in young patients. As a result, programs

17

should be developed to ensure a correct study and follow-up of patients (and their first-degree

relatives as well) likely to have the disease.

Sedentarism, dyslipidemia, hypertension, smoking and alcoholism remain some of the most

frequent problems in modern society and major contributors to a shorter lifespan. As such, it is

important to emphasize that BrS patients may have multiple comorbidities that continue to

require medical treatment after the diagnosis. However, their treatment must always take into

consideration the pharmacological restrictions that this disease requires.20,21 Regarding physical

exercise, a great number of patients had little or no physical activity, indicating that efforts

should be made to promote a healthy and active lifestyle, avoiding nevertheless vigorous

exercise.13

Therapeutic profile

Many drugs have been reported to induce potentially fatal arrhythmias in BrS patients. In this

study, more than half of the patients had taken at least one drug that is contraindicated or should

be avoided in BrS, with several patients taking multiple drugs. Metoclopramide was the most

incorrectly prescribed drug followed by tramadol and indapamide. Other identified drugs were

antidepressants such as amitriptiline, paroxetin and fluoxetin, and antiarrhytmic drugs (namely

propranolol, amiodarone, propafenone and flecainide). Since these drugs are responsible for an

increased risk for developing VF and ventricular tachycardia (VT)20,21, it is possible that a large

portion of the medical community is still unaware of the restrictions imposed by this disease.

Accordingly, it is crucial to educate the medical community about the existence of a written

document from www.brugadadrugs.org enumerating all non-recommended drugs, make certain

that it is given to the patients and ensure that the patients adhere to its contents.

The rate of appropriate ICD therapies was 4.0%/year (2.9%/year for appropriate shocks and

1.1%/year for ATP). Patients with appropriate ICD therapies had a tendency to be more

frequently treated with non-recommended drugs than patients without appropriate ICD

18

therapies. Furthermore, research of other drugs and herbal medicines potentially unsafe or with

a negative impact in the disease must continue.

Electrophysiological effects of the most taken non-recommended drugs

The various non-recommended drugs taken by this cohort have different electrophysiological

effects, some of which are yet to be truly understood.

Metoclopramide, the most wrongly prescribed drug, has a class IIb recommendation and should

be preferably avoided.20,21 Its arrhythmogenic mechanism involves cardiac sodium channels,

but the exact mode of action is still unknown.24

Indapamide and tramadol were the second most frequently used non-recommended drugs. Both

are considered preferably avoided drugs with a class IIb recommendation.20,21 Indapamide’s

electrophysiological effect derives both from the induction of hypokalemia (enhances the Ito

current and sustaining polymorphic VT and VF) and hyponatremia (possibly resulting in a

reduction of the INa currents, inducing type 1 Brugada pattern),25 whereas tramadol is known

to block sodium-channels in vitro.26,27

Type 2 DM and arrhythmic risk in Brugada syndrome

The effect of type 2 DM in BrS has yet to be determined. Nevertheless, previous studies found

that DM is linked with an increased risk of ventricular arrhythmias.28–30 Its proposed

mechanisms are an abnormal ventricular repolarization28 and sympathetic overstimulation as a

result of autonomic neuropathy28,30 and hypoglycemia.28,29 Furthermore, DM has been

consistently associated with ischemic heart disease and acute myocardial infarction, two

conditions that facilitate ventricular arrhythmias.31 Our study revealed no association between

appropriate ICD therapies and acute myocardial infarction or coronary artery disease syndrome,

potential confounding variables.

19

In our study patients with type 2 DM presented a significantly higher proportion of appropriate

ICD therapies than their counterparts. However, the arrhythmogenic potential of DM in

Brugada syndrome needs to be confirmed in further studies.

Limitations

One of the major limitations of this study was the sample size, mainly due to the fact that BrS

is a rare disease1–5,10,11 and that only a fraction of the patients require an ICD.1,3–5,10,11,17,18

Furthermore, the study was unicentric and retrospective and as a result, other factors that may

influence ICD therapies such as emotions, psychological states and daily activities were not

taken into consideration.

20

Conclusion

Our data revealed that most high-risk BrS patients took at least one non-recommended drug.

These patients had a higher tendency to have appropriate ICD therapies. Further efforts are

necessary to raise awareness in the medical community and in patients about unsafe drugs and

arrhythmic triggers that must be avoided.

Furthermore, type 2 DM was associated with a higher rate of appropriate ICD therapies.

Nevertheless, studies with larger cohorts are necessary to assess the real dimension of the

problem and to determine if type 2 DM is an independent predictor of arrhythmic events in BrS.

21

Acknowledgments

I would like to thank Natália António, M.D. Ph.D., for all her support and patience throughout

this process and for helping me surpass my boundaries.

I would also like to thank Marta Madeira, M.D., for all the help in the development and

reviewing of this project.

I thank my parents and brother for all the unconditional love, patience, caring, support and joy

they gave me during this project and throughout the years, and for making me believe in myself.

Finally, thank you, Mariana, for your unwavering support and love, for always being there for

me, and for making everything easier every step of the way.

22

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